Treatment for diabetes in patients with inadequate glycemic control despite metformin therapy comprising a DPP-IV inhibitor

ABSTRACT

The present invention relates to the finding that certain DPP-4 inhibitors are particularly suitable for improving glycemic control in type 2 diabetes patients with inadequate glycemic control despite metformin therapy.

The present invention relates to certain DPP-4 inhibitors for improvingglycemic control, such as e.g. improving hemoglobin A1c (HbA1c) and/orfasting plasma glucose (FPG), in type 2 diabetes patients withinadequate glycemic control despite therapy with metformin, as well asto the use of these DPP-4 inhibitors in antidiabetic therapy.Pharmaceutical compositions for treating and/or preventing metabolicdiseases (particularly diabetes, especially type 2 diabetes mellitus,and diseases related thereto) in these patients comprising a DPP-4inhibitor as defined herein optionally together with one or more otheractive substances are also contemplated.

Type 2 diabetes mellitus is a common chronic and progressive diseasearising from a complex pathophysiology involving the dual endocrineeffects of insulin resistance and impaired insulin secretion. Thetreatment of type 2 diabetes typically begins with diet and exercise,followed by oral antidiabetic monotherapy, and although conventionalmonotherapy may initially control blood glucose in some patients, it ishowever associated with a high secondary failure rate. The limitationsof single-agent therapy for maintaining glycemic control may beovercome, at least in some patients, and for a limited period of time bycombining multiple oral drugs to achieve reductions in blood glucosethat cannot be sustained during long-term therapy with single agents.Available data support the conclusion that in most patients with type 2diabetes monotherapy will fail and treatment with multiple drugs will berequired.

But, because type 2 diabetes is a progressive disease, even patientswith good initial responses to conventional combination therapy willeventually require an increase of the dosage or further treatment withinsulin because the blood glucose level is very difficult to maintainstable for a long period of time. Thus, although existing combinationtherapy has the potential to enhance glycemic control, it is not withoutlimitations (especially with regard to long term efficacy). Further,many results indicate that the risk for hypoglycemia and/or weight gainmay increase with conventional combination therapy, and the requirementfor multiple medications may also reduce patient compliance. Inaddition, taking multiple antihyperglycemic drugs may increase thepotential for pharmacokinetic interactions with other medications thatthe patient may be taking.

Thus, for many patients, these existing drug therapies result inprogressive deterioriation in glycemic control despite treatment and donot sufficiently control glycemia especially over long-term and thusfail to achieve and to maintain metabolic control e.g. in advanced orlate stage type 2 diabetes and/or in diabetes with secondary drugfailure.

Therefore, although intensive treatment of hyperglycemia can reduce theincidence of chronic damages, many patients with type 2 diabetes remaininadequately treated, partly because of limitations in long termefficacy, tolerability and dosing inconvenience of conventionalantihyperglycemic therapies.

This high incidence of therapeutic failure is a major contributor to thehigh rate of long-term hyperglycemia-associated complications or chronicdamages (including micro- and makrovascular complications such as e.g.diabetic nephrophathy, retinopathy or neuropathy, or cardiovascularcomplications) in patients with type 2 diabetes.

Oral antidiabetic drugs conventionally used in therapy (such as e.g.first- or second-line, and/or mono- or (initial or add-on) combinationtherapy) include, without being restricted thereto, metformin,sulphonylureas, thiazolidinediones, glinides and α-glucosidaseinhibitors.

Metformin is the drug of choice for beginning or first-line antidiabetictherapy (especially for overweight patients), unless there is risk ofrenal impairment, contraindication or intolerance to metformin.

However, as mentioned above, despite being on metformin therapy, somediabetic patients may fail to achieve or maintain glycemic control overtime.

Thus, according to clinical guidelines, when metformin alone fails tocontrol glucose concentrations to target levels, multiple othermedications, e.g. dual or triple combination treatments, become stepwisenecessary to improve glycemic control at least for a certain time, suchas e.g. as follows: When metformin monotherapy fails to control glucoseconcentrations to target levels (e.g. HbA1c>6.5%), in the first instanceeither a sulfonylurea (or a glinide) or a thiazolidinedione may be usedas add-on therapy to metformin. Furthermore, with further deterioriationin glycemic control, when also a combination of metformin and asulfonylurea fails to control glucose concentrations to target levels(e.g. HbA1c>6.5%), a thiazolidinedione may be used additionally to themetformin/sulfonylurea combination. Moreover, with yet furtherdeterioriation in glycemic control, when also the triple combination ofmetformin, a sulfonylurea and a thiazolidinedione fails to controlglucose concentrations to target levels (e.g. HbA1c>7.5%), ametformin/sulfonylurea combination may be used with once daily basalinsulin, or, in case of still yet further deterioration, metformin maybe used with twice daily premix insulin, or, finally, multiple dailyinsulin may be used.

A recommended standard medication for type 2 diabets patients withsuboptiomal glycemic control despite therapy with metformin alone, is acombination therapy taking a sulfonylurea and metformin, particularly asadd-on medication of the sulfonylurea to metformin background therapy.

Sulphonylureas (SU), as well as glinides, stimulate insulin secretionfrom pancreatic beta-cells in a non-glucose-dependent manner and aregenerally and frequentially used as a first- or second-line (mono- orcombination) treatment in type 2 diabetes (especially indicated fornon-obese patients and/or for patients ineligible for or with failure inmetformin therapy). However, as mentioned above, some patients do notalways respond well to these conventional oral antidiabetic agentsespecially in long-term treatment and may show insufficient ordeterioration in glycemic control despite treatment with a sulphonylureadrug (secondary SU failure). Also, patients on long-term sulfonylureatherapy experience a decline or an exhaustion in pancreatic beta cellfunction over time.

Continuing loss of efficacy over time is a major concern with the use ofinsulin secretagogues including glinides and sulfonylureas (secondary SUfailure). Furthermore, sulfonylureas increase plasma levels of insulinand may cause hypoglycaemia, which is—besides weight gain—one of theirmajor adverse effects, particularly in association with renal impairmentand/or in elderly patients. Thus, within SU medication, on the one side,with regard to efficacy, sometimes an increased sulfonylurea dose may berequired, whereas, on the other side, with regard tosafety/tolerability, sometimes a decreased sulfonylurea dose may berequired, thus requiring often an unsatisfying compromise in SUmedication.

Thus, the use of conventional antidiabetic combination therapies, e.g.combined metformin/sulfonylurea therapy, for treating type 2 diabetespatients with inadequate glycemic control on metformin alone has theirlimitations, such as e.g. by their inability to prevent progressivebeta-cell dysfunction and/or progressive loss of glycemic control, bythe risk of secondary failure and/or by the risk or incidence of adverseeffects associated with the medications such as e.g. hypoglycemicepisodes and/or weight gain.

Therefore, it remains a need in the art to provide efficacious, safe andtolerable antidiabetic therapies for type 2 diabetes mellitus patientswith inadequate glycemic control despite therapy with metformin.

Further, it remains a need in the art to provide adequate glycemiccontrol (e.g. to provide significant and relevant improvements in HbA1cand/or FPG) for diabetic patients with insufficient glycemic controldespite metformin therapy.

Moreover, since type 2 diabetes is a progressive chronic condition whichfrequently requires long-term treatment, physicians treating patientswith type 2 diabetes need to have a range of treatment and combinationregimens so they can tailor the therapy to the individual needs.

Furthermore, it is important that treatments not only prevent thelong-term complications often found in advanced stages of the diabetesdisease, but also prove to be a therapeutic option in those patients whohave developed complications, such as renal impairment.

HbA1c and FPG levels are key diagnostic measures of the effectivemanagement of type 2 diabetes.

In the monitoring of the treatment of diabetes mellitus the HbA1c value,the product of a non-enzymatic glycation of the haemoglobin B chain, isof exceptional importance. As its formation depends essentially on theblood sugar level and the life time of the erythrocytes the HbA1c in thesense of a “blood sugar memory” reflects the average blood sugar levelof the preceding 4-12 weeks. Diabetic patients whose HbA1c level hasbeen well controlled over a long time by more intensive diabetestreatment (i.e. <6.5% of the total haemoglobin in the sample) aresignificantly better protected from diabetic microangiopathy. Theavailable treatments for diabetes can give the diabetic an averageimprovement in their HbA1c level of the order of 1.0-1.5%. Thisreduction in the HbA1C level is not sufficient in all diabetics to bringthem into the desired target range of <7.0%, preferably <6.5% and morepreferably <6% HbA1c.

Within glycemic control, in addition to improvement of the HbA1c level,other recommended therapeutic goals for type 2 diabetes mellituspatients are improvement of fasting plasma glucose (FPG) and ofpostprandial plasma glucose (PPG) levels to normal or as near normal aspossible. Recommended desired target ranges of preprandial (fasting)plasma glucose are 70-130 mg/dL (or 90-130 mg/dL) or <110 mg/dL, and oftwo-hour postprandial plasma glucose are <180 mg/dL or <140 mg/dL.

Within the meaning of this invention, patients with inadequate orinsufficient glycemic control despite a therapy with metformin include,without being limited to, patients having a HbA1c value from 7.5 to 10%(or, in another embodiment, from 7.5 to 11%) at baseline despitetreatment with metformin, particularly despite medication with ≧1 gmetformin per day.

A special sub-embodiment of inadequately controlled patients within themeaning of this invention refers to patients in advanced or late stagetype 2 diabetes patients and/or with poor glycemic control including,without being limited, patients having a HbA1c value ≧9% at baseline.

The enzyme DPP-4 (dipeptidyl peptidase IV) also known as CD26 is aserine protease known to lead to the cleavage of a dipeptide from theN-terminal end of a number of proteins having at their N-terminal end aprolin or alanin residue. Due to this property DPP-4 inhibitorsinterfere with the plasma level of bioactive peptides including thepeptide GLP-1 and are considered to be promising drugs for the treatmentof diabetes mellitus.

For example, DPP-4 inhibitors and their uses, particularly their uses inmetabolic (especially diabetic) diseases, are disclosed in WO2002/068420, WO 2004/018467, WO 2004/018468, WO 2004/018469, WO2004/041820, WO 2004/046148, WO 2005/051950, WO 2005/082906, WO2005/063750, WO 2005/085246, WO 2006/027204, WO 2006/029769 orWO2007/014886; or in WO 2004/050658, WO 2004/111051, WO 2005/058901 orWO 2005/097798; or in WO 2006/068163, WO 2007/071738 or WO 2008/017670;or in WO 2007/128721 or WO 2007/128761.

As further DPP-4 inhibitors the following compounds can be mentioned:

-   -   Sitagliptin (MK-0431) having the structural formula A below is        (3R)-3-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one,        also named        (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine,

In one embodiment, sitagliptin is in the form of its dihydrogenphosphatesalt, i.e. sitagliptin phosphate. In a further embodiment, sitagliptinphosphate is in the form of a crystalline anhydrate or monohydrate. Aclass of this embodiment refers to sitagliptin phosphate monohydrate.Sitagliptin free base and pharmaceutically acceptable salts thereof aredisclosed in U.S. Pat. No. 6,699,871 and in Example 7 of WO 03/004498.Crystalline sitagliptin phosphate monohydrate is disclosed in WO2005/003135 and in WO 2007/050485.

For details, e.g. on a process to manufacture, to formulate or to usethis compound or a salt thereof, reference is thus made to thesedocuments.

A tablet formulation for sitagliptin is commercially available under thetrade name Januvia®. A tablet formulation for sitagliptin/metformincombination is commercially available under the trade name Janumet®.

-   -   Vildagliptin (LAF-237) having the structural formula B below is        (2S)-{[(3-hydroxyadamantan-1-yl)amino]acetyl}pyrrolidine-2-carbonitrile,        also named        (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-pyrrolidine,

Vildagliptin is specifically disclosed in U.S. Pat. No. 6,166,063 and inExample 1 of WO 00/34241. Specific salts of vildagliptin are disclosedin WO 2007/019255. A crystalline form of vildagliptin as well as avildagliptin tablet formulation are disclosed in WO 2006/078593.Vildagliptin can be formulated as described in WO 00/34241 or in WO2005/067976. A modified release vildagliptin formulation is described inWO 2006/135723.

For details, e.g. on a process to manufacture, to formulate or to usethis compound or a salt thereof, reference is thus made to thesedocuments.

A tablet formulation for vildagliptin is commercially available underthe trade name Galvus®. A tablet formulation for vildagliptin/metformincombination is commercially available under the trade name Eucreas®.

-   -   Saxagliptin (BMS-477118) having the structural formula C below        is        (1S,3S,5S)-2-{(2S)-2-amino-2-(3-hydroxyadamantan-1-yl)acetyl}-2-azabicyclo[3.1.0]hexane-3-carbonitrile,        also named        (S)-3-hydroxyadamantylglycine-L-cis-4,5-methanoprolinenitrile,

Saxagliptin is specifically disclosed in U.S. Pat. No. 6,395,767 and inExample 60 of WO 01/68603.

In one embodiment, saxagliptin is in the form of its HCl salt or itsmono-benzoate salt as disclosed in WO 2004/052850. In a furtherembodiment, saxagliptin is in the form of the free base. In a yetfurther embodiment, saxagliptin is in the form of the monohydrate of thefree base as disclosed in WO 2004/052850. Crystalline forms of the HClsalt and the free base of saxagliptin are disclosed in WO 2008/131149. Aprocess for preparing saxagliptin is also disclosed in WO 2005/106011and WO 2005/115982. Saxagliptin can be formulated in a tablet asdescribed in WO 2005/117841.

For details, e.g. on a process to manufacture, to formulate or to usethis compound or a salt thereof, reference is thus made to thesedocuments.

-   -   Alogliptin (SYR-322) having the structural formula E below is        2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl}methyl)benzonitrile

Alogliptin is specifically disclosed in US 2005/261271, EP 1586571 andin WO 2005/095381. In one embodiment, alogliptin is in the form of itsbenzoate salt, its hydrochloride salt or its tosylate salt each asdisclosed in WO 2007/035629. A class of this embodiment refers toalogliptin benzoate. Polymorphs of alogliptin benzoate are disclosed inWO 2007/035372. A process for preparing alogliptin is disclosed in WO2007/112368 and, specifically, in WO 2007/035629. Alogliptin (namely itsbenzoate salt) can be formulated in a tablet and administered asdescribed in WO 2007/033266. Formulations of Aloglipitin withpioglitazone or metformin are described in WO 2008/093882 or WO2009/011451, respectively. For details, e.g. on a process tomanufacture, to formulate or to use this compound or a salt thereof,reference is thus made to these documents.

-   -   (2S)-1-{[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrile        or a pharmaceutically acceptable salt thereof, preferably the        mesylate, or        (2S)-1-{[1,1,-Dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino]-acetyl}-pyrrolidine-2-carbonitrile        or a pharmaceutically acceptable salt thereof:

These compounds and methods for their preparation are disclosed in WO03/037327. The mesylate salt of the former compound as well ascrystalline polymorphs thereof are disclosed in WO 2006/100181. Thefumarate salt of the latter compound as well as crystalline polymorphsthereof are disclosed in WO 2007/071576. These compounds can beformulated in a pharmaceutical composition as described in WO2007/017423.

For details, e.g. on a process to manufacture, to formulate or to usethese compounds or salts thereof, reference is thus made to thesedocuments.

-   -   (S)-1-((2S,3S,11bS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one        or a pharmaceutically acceptable salt thereof:

This compound and methods for its preparation are disclosed in WO2005/000848. A process for preparing this compound (specifically itsdihydrochloride salt) is also disclosed in WO 2008/031749, WO2008/031750 and WO 2008/055814. This compound can be formulated in apharmaceutical composition as described in WO 2007/017423.

For details, e.g. on a process to manufacture, to formulate or to usethis compound or a salt thereof, reference is thus made to thesedocuments.

-   -   (3,3-Difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone        (also named gosogliptin) or a pharmaceutically acceptable salt        thereof:

This compound and methods for its preparation are disclosed in WO2005/116014 and U.S. Pat. No. 7,291,618.

For details, e.g. on a process to manufacture, to formulate or to usethis compound or a salt thereof, reference is thus made to thesedocuments.

-   -   (1((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5-difluoropiperidin-2-one        or a pharmaceutically acceptable salt thereof:

This compound and methods for its preparation are disclosed in WO2007/148185 and

US 20070299076. For details, e.g. on a process to manufacture, toformulate or to use this compound or a salt thereof, reference is thusmade to these documents.

-   -   (2S,4S)-1-{2-[(3S,1R)-3-(1H-1,2,4-Triazol-1-ylmethyl)cyclopentylamino]acetyl}-4-fluoropyrrolidine-2-carbonitrile        (also named melogliptin) or a pharmaceutically acceptable salt        thereof:

This compound and methods for its preparation are disclosed in WO2006/040625 and WO 2008/001195. Specifically claimed salts include themethanesulfonate and p-toluenesulfonate. For details, e.g. on a processto manufacture, to formulate or to use this compound or a salt thereof,reference is thus made to these documents.

-   -   (R)-2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile        or a pharmaceutically acceptable salt thereof:

This compound and methods for its preparation and use are disclosed inWO 2005/095381, US 2007060530, WO 2007/033350, WO 2007/035629, WO2007/074884, WO 2007/112368, WO 2008/033851, WO 2008/114800 and WO2008/114807. Specifically claimed salts include the succinate (WO2008/067465), benzoate, benzenesulfonate, p-toluenesulfonate,(R)-mandelate and hydrochloride. For details, e.g. on a process tomanufacture, to formulate or to use this compound or a salt thereof,reference is thus made to these documents.

-   -   5-{(S)-2-[2-((S)-2-Cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-propyl}-5-(1H-tetrazol-5-yl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic        acid bis-dimethylamide or a pharmaceutically acceptable salt        thereof:

This compound and methods for its preparation are disclosed in WO2006/116157 and US 2006/270701. For details, e.g. on a process tomanufacture, to formulate or to use this compound or a salt thereof,reference is thus made to these documents.

-   -   3-{(2S,4S)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine        (also named teneligliptin) or a pharmaceutically acceptable salt        thereof:

This compound and methods for its preparation are disclosed in WO02/14271. Specific salts are disclosed in WO 2006/088129 and WO2006/118127 (including hydrochloride, hydrobromide, inter alia).Combination therapy using this compound is described in WO 2006/129785.For details, e.g. on a process to manufacture, to formulate or to usethis compound or a salt thereof, reference is thus made to thesedocuments.

-   -   [(2R)-1-{[(3R)-pyrrolidin-3-ylamino]acetyl}pyrrolidin-2-yl]boronic        acid (also named dutogliptin) or a pharmaceutically acceptable        salt thereof:

This compound and methods for its preparation are disclosed in WO2005/047297, WO 2008/109681 and WO 2009/009751. Specific salts aredisclosed in WO 2008/027273 (including citrate, tartrate). A formulationof this compound is described in WO 2008/144730. For details, e.g. on aprocess to manufacture, to formulate or to use this compound or a saltthereof, reference is thus made to these documents.

-   -   (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile        or a pharmaceutically acceptable salt thereof:

This compound and methods for its preparation are disclosed in WO2005/075421, US 2008/146818 and WO 2008/114857. For details, e.g. on aprocess to manufacture, to formulate or to use this compound or a saltthereof, reference is thus made to these documents.

-   -   2-({6-[(3R)-3-amino-3-methylpiperidin-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile        or a pharmaceutically acceptable salt thereof, or        6-[(3R)-3-amino-piperidin-1-yl]-5-(2-chloro-5-fluoro-benzyl)-1,3-dimethyl-1,5-dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione        or a pharmaceutically acceptable salt thereof:

These compounds and methods for their preparation are disclosed in WO2009/084497 and WO 2006/068163, respectively. For details, e.g. on aprocess to manufacture, to formulate or to use these compounds or saltsthereof, reference is thus made to these documents.

For avoidance of any doubt, the disclosure of each of the foregoingdocuments cited above is specifically incorporated herein by referencein its entirety.

Within the scope of the present invention it has now surprisingly beenfound that certain DPP-4 inhibitors as defined herein have unexpectedand particularly advantageous properties, which make them particularlysuitable for improving glycemic control in patients with type 2 diabetesmellitus inadequately controlled on metformin alone.

Further in this context, it has surprisingly been found that with acertain dose of a DPP-4 inhibitor, such as for example 5 mg BI 1356administered orally once daily, maximum reduction of HbA1c and/or FPGcan be achieved, thus providing a therapeutic dose.

From dose-response study with 1, 5 and 10 mg once daily oral dosing ofBI 1356 added to ongoing metformin therapy in patients with type 2diabetes and insufficient glycemic control, 12 weeks treatment with BI1356 results in clinically relevant reductions in HbA1c and FPG comparedwith baseline for all BI 1356 doses (1, 5 and 10 mg) and lower HbA1c andFPG compared levels compared to placebo. It appears that maximumglucose-lowering effects are reached after 8 weeks with a plateauthereafter. 5 mg BI 1356 daily provides in the patients the maximumglycemic effect with up to greatest percentage of patients achieving thetargets of a HbA1c lowering of at least 0.5% from baseline (≧0.5%:53.2%,≧1.0%:27.4%) and of a HbA1c value of ≦57.0% (14.5%).

Further in this context, it has surprisingly been found that a dose of aDPP-4 inhibitor resulting in >80% DPP-4 inhibition in >80% of thepatients at trough, such as for example 5 mg BI 1356 administered orallyonce daily, is a therapeutic dose.

Further, it has been found that a greater portion of patients of thisinvention demonstrating clinically meaningful changes in HbA1c (≧0.5%)are in those who have higher baseline HbA1c levels (≧9%).

Thus, the present invention provides a DPP-4 inhibitor as defined hereinfor use in improving glycemic control in type 2 diabetes patients withinadequate glycemic control despite metformin therapy, particularlydespite monotherapy with metformin, for example despite maximaltolerated dose of oral therapy with metformin.

A special embodiment of this invention refers to a DPP-4 inhibitor asdefined herein for use in improving glycemic control in type 2 diabetespatients with inadequate glycemic control despite metformin therapy,wherein said DPP-4 inhibitor reduces significantly glycosylatedhaemoglobin HbA1c and/or fasting plasma glucose.

Another special embodiment of this invention refers to a DPP-4 inhibitoras defined herein for use in improving glycemic control in type 2diabetes patients with inadequate glycemic control despite metformintherapy, wherein said DPP-4 inhibitor may be used as add-on or initialcombination therapy with metformin, particularly as add-on combinationtherapy with metformin.

Another special embodiment of this invention refers to a DPP-4 inhibitoras defined herein for use in reducing significantly glycosylatedhaemoglobin HbA1c and/or fasting plasma glucose in type 2 diabetespatients with inadequate glycemic control on metformin alone, whereinsaid DPP-4 inhibitor is administered to said patients in an amount from1 mg to 10 mg once daily, particularly 5 mg once daily, over 12 weeks asadd-on to metformin background therapy.

The present invention further provides a DPP-4 inhibitor as definedherein for resulting in >80% DPP-4 inhibition at trough in >80% of type2 diabetes patients with inadequate glycemic control having HbA1c atbaseline from 7.5 to 10% despite mono-medication with ≧1 g metformin perday, wherein said DPP-4 inhibitor is administered over 12 weeks in anamount of 5 mg orally once daily as add-on to metformin backgroundtherapy.

The present invention further provides a DPP-4 inhibitor as definedherein for use in the treatment and/or prevention (including preventingor slowing the progression or delaying the onset) of metabolic diseases,particularly diabetes (especially type 2 diabetes mellitus) and diseasesrelated thereto (e.g. diabetic complications), in patients withinadequate glycemic control despite therapy with metformin, particularlydespite monotherapy with metformin.

The present invention further provides a pharmaceutical composition foruse in the therapies described herein in patients with insufficientglycemic control despite treatment with metformin, said pharmaceuticalcomposition comprising a DPP-4 inhibitor as defined herein andoptionally one or more pharmaceutically acceptable carriers and/ordiluents.

The present invention further provides a fixed or non-fixed combinationincluding a kit-of-parts for use in the therapies described herein inpatients with insufficient glycemic control despite therapy withmetformin, said combination comprising a DPP-4 inhibitor as definedherein and one or more other active substances, e.g. any of thosementioned herein.

The present invention further provides the use of a DPP-4 inhibitor asdefined herein optionally in combination with one or more other activesubstances, such as e.g. any of those mentioned herein, for themanufacture of a pharmaceutical composition for the therapies describedherein, in patients with insufficient glycemic control despite therapywith metformin.

The present invention further provides a pharmaceutical composition foruse in the therapies described herein in patients with insufficientglycemic control despite therapy with metformin, said pharmaceuticalcomposition comprising a DPP-4 inhibitor as defined herein andoptionally one or more other active substances, such as e.g. any ofthose mentioned herein.

The present invention further provides a method of treating and/orpreventing metabolic diseases, particularly type 2 diabetes mellitus, inpatients with insufficient glycemic control despite therapy withmetformin, said method comprising administering to a subject in needthereof (particularly a human patient) an effective amount of a DPP-4inhibitor as defined herein, optionally separately, sequentially,simultaneously, concurrently or chronologically staggered with aneffective amount of one or more other active substances, such as e.g.any of those mentioned herein.

Further, the DPP-4 inhibitors as defined herein may be useful in one ormore of the following methods

-   -   for preventing, slowing progression of, delaying, or treating a        metabolic disorder;    -   for improving glycemic control and/or for reducing of fasting        plasma glucose, of postprandial plasma glucose and/or of        glycosylated hemoglobin HbA1c;    -   for preventing, slowing progression of, delaying or treating of        a condition or disorder selected from the group consisting of        complications of diabetes mellitus;    -   for reducing the weight or preventing an increase of the weight        or facilitating a reduction of the weight;    -   for preventing or treating the degeneration of pancreatic beta        cells and/or for improving and/or restoring the functionality of        pancreatic beta cells and/or stimulating and/or restoring the        functionality of pancreatic insulin secretion; and/or    -   for maintaining and/or improving the insulin sensitivity and/or        for treating or preventing hyperinsulinemia and/or insulin        resistance;        in diabetes patients with inadequate glycemic control despite        therapy with metformin.

Examples of such metabolic diseases or disorders amenable by the therapyof this invention in patients with insufficient glycemic control despitemetformin therapy may include, without being restricted to, Type 1diabetes, Type 2 diabetes, inadequate glucose tolerance, insulinresistance, hyperglycemia, hyperlipidemia, hypercholesterolemia,dyslipidemia, metabolic syndrome X, obesity, hypertension, chronicsystemic inflammation, retinopathy, neuropathy, nephropathy,atherosclerosis, endothelial dysfunction and osteoporosis.

The present invention further provides a DPP-4 inhibitor as definedherein, optionally in combination with one or more other activesubstances, such as e.g. any of those mentioned herein, for use in oneor more of the following methods:

-   -   preventing, slowing the progression of, delaying or treating a        metabolic disorder or disease, such as e.g. type 1 diabetes        mellitus, type 2 diabetes mellitus, impaired glucose tolerance        (IGT), impaired fasting blood glucose (IFG), hyperglycemia,        postprandial hyperglycemia, overweight, obesity, dyslipidemia,        hyperlipidemia, hypercholesterolemia, hypertension,        atherosclerosis, endothelial dysfunction, osteoporosis, chronic        systemic inflammation, non alcoholic fatty liver disease        (NAFLD), retinopathy, neuropathy, nephropathy and/or metabolic        syndrome;    -   improving glycemic control and/or for reducing of fasting plasma        glucose, of postprandial plasma glucose and/or of glycosylated        hemoglobin HbA1c;    -   preventing, slowing, delaying or reversing progression from        impaired glucose tolerance (IGT), impaired fasting blood glucose        (IFG), insulin resistance and/or from metabolic syndrome to type        2 diabetes mellitus;    -   preventing, reducing the risk of, slowing the progression of,        delaying or treating of complications of diabetes mellitus such        as micro- and macrovascular diseases, such as nephropathy,        micro- or macroalbuminuria, proteinuria, retinopathy, cataracts,        neuropathy, learning or memory impairment, neurodegenerative or        cognitive disorders, cardio- or cerebrovascular diseases, tissue        ischaemia, diabetic foot or ulcus, atherosclerosis,        hypertension, endothelial dysfunction, myocardial infarction,        acute coronary syndrome, unstable angina pectoris, stable angina        pectoris, peripheral arterial occlusive disease, cardiomyopathy,        heart failure, heart rhythm disorders, vascular restenosis,        and/or stroke;    -   reducing body weight or preventing an increase in body weight or        facilitating a reduction in body weight;    -   preventing, slowing, delaying or treating the degeneration of        pancreatic beta cells and/or the decline of the functionality of        pancreatic beta cells and/or for improving and/or restoring the        functionality of pancreatic beta cells and/or stimulating and/or        restoring the functionality of pancreatic insulin secretion;    -   preventing, slowing, delaying or treating non alcoholic fatty        liver disease (NAFLD) including hepatic steatosis, non-alcoholic        steatohepatitis (NASH) and/or liver fibrosis;    -   preventing, slowing the progression of, delaying or treating        type 2 diabetes with failure to conventional antidiabetic mono-        or combination therapy;    -   achieving a reduction in the dose of conventional antidiabetic        medication required for adequate therapeutic effect;    -   reducing the risk for adverse effects associated with        conventional antidiabetic medication; and/or    -   maintaining and/or improving the insulin sensitivity and/or for        treating or preventing hyperinsulinemia and/or insulin        resistance;        particularly in a patient with inadequate glycemic control        despite therapy with metformin.

Other aspects of the present invention become apparent to the skilledperson from the foregoing and following remarks.

A DPP-4 inhibitor within the meaning of the present invention includes,without being limited to, any of those DPP-4 inhibitors mentionedhereinabove and hereinbelow, preferably orally active DPP-4 inhibitors.

For example, a DPP-4 inhibitor according to this invention may be suchan oral DPP-4 inhibitor, which and whose active metabolites havepreferably a relatively wide (e.g. about >100 fold) therapeutic windowand/or, especially, that are primarily eliminated via hepatic metabolismor biliary excretion.

In more detailed example, a DPP-4 inhibitor according to this inventionmay be such an orally administered DPP-4 inhibitor, which has arelatively wide (e.g. >100 fold) therapeutic window and/or which fulfilsone or more of the following pharmacokinetic properties (preferably atits therapeutic oral dose levels):

-   -   The DPP-4 inhibitor is substantially or mainly excreted via the        liver (e.g. >80% or even >90% of the administered oral dose),        and/or for which renal excretion represents no substantial or        only a minor elimination pathway (e.g. <10%, preferably <7%, of        the administered oral dose measured, for example, by following        elimination of a radiolabelled carbon (¹⁴C) substance oral        dose);    -   The DPP-4 inhibitor is excreted mainly unchanged as parent drug        (e.g. with a mean of >70%, or >80%, or, preferably, 90% of        excreted radioactivity in urine and faeces after oral dosing of        radiolabelled carbon (¹⁴C) substance), and/or which is        eliminated to a non-substantial or only to a minor extent via        metabolism (e.g. <30%, or <20%, or, preferably, 10%);    -   The (main) metabolite(s) of the DPP-4 inhibitor is/are        pharmacologically inactive. Such as e.g. the main metabolite        does not bind to the target enzyme DPP-4 and, optionally, it is        rapidly eliminated compared to the parent compound (e.g. with a        terminal half-life of the metabolite of ≦20 h, or, preferably,        ≦about 16 h, such as e.g. 15.9 h).

In one embodiment, the (main) metabolite in plasma (which may bepharmacologically inactive) of a DPP-4 inhibitor having a3-amino-piperidin-1-yl substituent is such a derivative where the aminogroup of the 3-amino-piperidin-1-yl moiety is replaced by a hydroxylgroup to form the 3-hydroxy-piperidin-1-yl moiety (e.g. the3-(S)-hydroxy-piperidin-1-yl moiety, which is formed by inversion of theconfiguration of the chiral center).

Further properties of a DPP-4 inhibitor according to this invention maybe one or more of the following: Rapid attainment of steady state (e.g.reaching steady state plasma levels (>90% of the steady state plasmaconcentration) between second and fifth day of treatment withtherapeutic oral dose levels), little accumulation (e.g. with a meanaccumulation ratio R_(A,AUC)≦1.4 with therapeutic oral dose levels),and/or preserving a long-lasting effect on DPP-4 inhibition, preferablywhen used once-daily (e.g. with almost complete (>90%) DPP-4 inhibitionat therapeutic oral dose levels, >80% inhibition over a 24 h intervalafter once-daily intake of therapeutic oral drug dose), significantdecrease in 2 h postprandial blood glucose excursions by ≧80% (alreadyon first day of therapy) at therapeutic dose levels, and cumulativeamount of unchanged parent compound excreted in urine on first day beingbelow 1% of the administered dose and increasing to not more than about3-6% in steady state.

Thus, for example, a DPP-4 inhibitor according to this invention may becharacterized in that said DPP-4 inhibitor is excreted to anon-substantial or only to a minor extent (e.g. <10%, preferably <7% ofadministered oral dose) via the kidney (measured, for example, byfollowing elimination of a radiolabelled carbon (¹⁴C) substance oraldose).

Further, a DPP-4 inhibitor according to this invention may becharacterized in that said DPP-4 inhibitor is excreted substantially ormainly via the liver (measured, for example, by following elimination ofa radiolabelled carbon (¹⁴C) substance oral dose).

Further, a DPP-4 inhibitor according to this invention may becharacterized in that said DPP-4 inhibitor is excreted mainly unchangedas parent drug (e.g. with a mean of >70%, or >80%, or, preferably, 90%of excreted radioactivity in urine and faeces after oral dosing ofradiolabelled carbon (¹⁴C) substance),

said DPP-4 inhibitor is eliminated to a non-substantial or only to aminor extent via metabolism, and/orthe main metabolite of said DPP-4 inhibitor is pharmacologicallyinactive or has a relatively wide therapeutic window.

In a first embodiment (embodiment A), a DPP-4 inhibitor in the contextof the present invention is any DPP-4 inhibitor of

wherein R1 denotes ([1,5]naphthyridin-2-yl)methyl,(quinazolin-2-yl)methyl, (quinoxalin-6-yl)methyl,(4-methyl-quinazolin-2-yl)methyl, 2-cyano-benzyl,(3-cyano-quinolin-2-yl)methyl, (3-cyano-pyridin-2-yl)methyl,(4-methyl-pyrimidin-2-yl)methyl, or (4,6-dimethyl-pyrimidin-2-yl)methyland R2 denotes 3-(R)-amino-piperidin-1-yl,(2-amino-2-methyl-propyl)-methylamino or(2-(S)-amino-propyl)-methylamino,or its pharmaceutically acceptable salt.

In a second embodiment (embodiment B), a DPP-4 inhibitor in the contextof the present invention is a DPP-4 inhibitor selected from the groupconsisting of sitagliptin, vildagliptin, saxagliptin, alogliptin,

-   (2S)-1-{[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrile,-   (2S)-1-{[1,1,-Dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino]-acetyl}-pyrrolidine-2-carbonitrile,-   (S)-1-((2S,3S,11bS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one,-   (3,3-Difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone,-   (1((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5-difluoropiperidin-2-one,-   (2S,4S)-1-{2-[(3S,1R)-3-(1H-1,2,4-Triazol-1-ylmethyl)cyclopentylamino]-acetyl}-4-fluoropyrrolidine-2-carbonitrile,-   (R)-2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile,-   5-{(S)-2-[2-((S)-2-Cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-propyl}-5-(1H-tetrazol-5-yl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic    acid bis-dimethylamide,-   3-{(2S,4S)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine,-   [(2R)-1-{[(3R)-pyrrolidin-3-ylamino]acetyl}pyrrolidin-2-yl]boronic    acid,-   (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile,-   2-({6-[(3R)-3-amino-3-methylpiperidin-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile,    and-   6-[(3R)-3-amino-piperidin-1-yl]-5-(2-chloro-5-fluoro-benzyl)-1,3-dimethyl-1,5-dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione,    or its pharmaceutically acceptable salt.

Regarding the first embodiment (embodiment A), preferred DPP-4inhibitors are any or all of the following compounds and theirpharmaceutically acceptable salts:

-   1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine    (compare WO 2004/018468, example 2(142)):

-   1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2004/018468, example 2(252)):

-   1-[(Quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2004/018468, example 2(80)):

-   2-((R)-3-Amino-piperidin-1-yl)-3-(but-2-yinyl)-5-(4-methyl-quinazolin-2-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one    (compare WO 2004/050658, example 136):

-   1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyin-1-yl)-8-[(2-amino-2-methyl-propyl)-methylamino]-xanthine    (compare WO 2006/029769, example 2(1)):

-   1-[(3-Cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2005/085246, example 1(30)):

-   1-(2-Cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2005/085246, example 1(39)):

-   1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-(2-amino-propyl)-methylamino]-xanthine    (compare WO 2006/029769, example 2(4)):

-   1-[(3-Cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2005/085246, example 1(52)):

-   1-[(4-Methyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2005/085246, example 1(81)):

-   1-[(4,6-Dimethyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2005/085246, example 1(82)):

-   1-[(Quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2005/085246, example 1(83)):

These DPP-4 inhibitors are distinguished from structurally comparableDPP-4 inhibitors, as they combine exceptional potency and a long-lastingeffect with favourable pharmacological properties, receptor selectivityand a favourable side-effect profile or bring about unexpectedtherapeutic advantages or improvements when combined with otherpharmaceutical active substances. Their preparation is disclosed in thepublications mentioned.

A more preferred DPP-4 inhibitor among the abovementioned DPP-4inhibitors of embodiment A of this invention is1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine,particularly the free base thereof (which is also known as BI 1356).

Unless otherwise noted, according to this invention it is to beunderstood that the definitions of the active compounds (including theDPP-4 inhibitors) mentioned hereinabove and hereinbelow also comprisetheir pharmaceutically acceptable salts as well as hydrates, solvatesand polymorphic forms thereof. With respect to salts, hydrates andpolymorphic forms thereof, particular reference is made to those whichare referred to herein.

With respect to embodiment A, the methods of synthesis for the DPP-4inhibitors according to embodiment A of this invention are known to theskilled person. Advantageously, the DPP-4 inhibitors according toembodiment A of this invention can be prepared using synthetic methodsas described in the literature. Thus, for example, purine derivatives offormula (I) can be obtained as described in WO 2002/068420, WO2004/018468, WO 2005/085246, WO 2006/029769 or WO 2006/048427, thedisclosures of which are incorporated herein. Purine derivatives offormula (II) can be obtained as described, for example, in WO2004/050658 or WO 2005/110999, the disclosures of which are incorporatedherein. Purine derivatives of formula (III) and (IV) can be obtained asdescribed, for example, in WO 2006/068163, WO 2007/071738 or WO2008/017670, the disclosures of which are incorporated herein. Thepreparation of those DPP-4 inhibitors, which are specifically mentionedhereinabove, is disclosed in the publications mentioned in connectiontherewith. Polymorphous crystal modifications and formulations ofparticular DPP-4 inhibitors are disclosed in WO 2007/128721 and WO2007/128724, respectively, the disclosures of which are incorporatedherein in their entireties. Formulations of particular DPP-4 inhibitorswith metformin or other combination partners are described in WO2009/121945, the disclosure of which is incorporated herein in itsentirety. Typical dosage strengths of the dual fixed combination of BI1356/metformin are 2.5/500 mg, 2.5/850 mg and 2.5/1000 mg, which may beadministered 1-3 times a day, particularly twice a day.

With respect to embodiment B, the methods of synthesis for the DPP-4inhibitors of embodiment B are described in the scientific literatureand/or in published patent documents, particularly in those citedherein.

For pharmaceutical application in warm-blooded vertebrates, particularlyhumans, the compounds of this invention are usually used in dosages from0.001 to 100 mg/kg body weight, preferably at 0.1-15 mg/kg, in each case1 to 4 times a day. For this purpose, the compounds, optionally combinedwith other active substances, may be incorporated together with one ormore inert conventional carriers and/or diluents, e.g. with corn starch,lactose, glucose, microcrystalline cellulose, magnesium stearate,polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol,water/glycerol, water/sorbitol, water/polyethylene glycol, propyleneglycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substancessuch as hard fat or suitable mixtures thereof into conventional galenicpreparations such as plain or coated tablets, capsules, powders,suspensions or suppositories.

The pharmaceutical compositions according to this invention comprisingthe DPP-4 inhibitors as defined herein are thus prepared by the skilledperson using pharmaceutically acceptable formulation excipients asdescribed in the art. Examples of such excipients include, without beingrestricted to diluents, binders, carriers, fillers, lubricants, flowpromoters, crystallisation retardants, disintegrants, solubilizers,colorants, pH regulators, surfactants and emulsifiers.

Examples of suitable diluents for compounds according to embodiment Ainclude cellulose powder, calcium hydrogen phosphate, erythritol, lowsubstituted hydroxypropyl cellulose, mannitol, pregelatinized starch orxylitol.

Examples of suitable lubricants for compounds according to embodiment Ainclude talc, polyethyleneglycol, calcium behenate, calcium stearate,hydrogenated castor oil or magnesium stearate.

Examples of suitable binders for compounds according to embodiment Ainclude copovidone (copolymerisates of vinylpyrrolidon with othervinylderivates), hydroxypropyl methylcellulose (HPMC),hydroxypropylcellulose (HPC), polyvinylpyrrolidon (povidone),pregelatinized starch, or low-substituted hydroxypropylcellulose(L-HPC).

Examples of suitable disintegrants for compounds according to embodimentA include corn starch or crospovidone.

Suitable methods of preparing pharmaceutical formulations of the DPP-4inhibitors according to embodiment A of the invention are

-   -   direct tabletting of the active substance in powder mixtures        with suitable tabletting excipients;    -   granulation with suitable excipients and subsequent mixing with        suitable excipients and subsequent tabletting as well as film        coating; or    -   packing of powder mixtures or granules into capsules.

Suitable granulation methods are

-   -   wet granulation in the intensive mixer followed by fluidised bed        drying;    -   one-pot granulation;    -   fluidised bed granulation; or    -   dry granulation (e.g. by roller compaction) with suitable        excipients and subsequent tabletting or packing into capsules.

An exemplary composition of a DPP-4 inhibitor according to embodiment Aof the invention comprises the first diluent mannitol, pregelatinizedstarch as a second diluent with additional binder properties, the bindercopovidone, the disintegrant corn starch, and magnesium stearate aslubricant; wherein copovidone and/or corn starch may be optional.

For details on dosage forms, formulations and administration of DPP-4inhibitors of this invention, reference is made to scientific literatureand/or published patent documents, particularly to those cited herein.

The pharmaceutical compositions (or formulations) may be packaged in avariety of ways. Generally, an article for distribution includes acontainer that contains the pharmaceutical composition in an appropriateform. Tablets are typically packed in an appropriate primary package foreasy handling, distribution and storage and for assurance of properstability of the composition at prolonged contact with the environmentduring storage. Primary containers for tablets may be bottles or blisterpacks.

A suitable bottle, e.g. for a pharmaceutical composition or combinationcomprising a DPP-4 inhibitor according to embodiment A of the invention,may be made from glass or polymer (preferably polypropylene (PP) or highdensity polyethylene (HD-PE)) and sealed with a screw cap. The screw capmay be provided with a child resistant safety closure (e.g.press-and-twist closure) for preventing or hampering access to thecontents by children. If required (e.g. in regions with high humidity),by the additional use of a desiccant (such as e.g. bentonite clay,molecular sieves, or, preferably, silica gel) the shelf life of thepackaged composition can be prolonged.

A suitable blister pack, e.g. for a pharmaceutical composition orcombination comprising a DPP-4 inhibitor according to embodiment A ofthe invention, comprises or is formed of a top foil (which is breachableby the tablets) and a bottom part (which contains pockets for thetablets). The top foil may contain a metalic foil, particularly analuminium or aluminium alloy foil (e.g. having a thickness of 20 μm to45 μm, preferably 20 μm to 25 μm) that is coated with a heat-sealingpolymer layer on its inner side (sealing side). The bottom part maycontain a multi-layer polymer foil (such as e.g. poly(vinyl chloride)(PVC) coated with poly(vinylidene chloride) (PVDC); or a PVC foillaminated with poly(chlorotrifluoroethylene) (PCTFE)) or a multi-layerpolymer-metal-polymer foil (such as e.g. a cold-formable laminatedPVC/aluminium/polyamide composition).

The article may further comprise a label or package insert, which referto instructions customarily included in commercial packages oftherapeutic products, that may contain information about theindications, usage, dosage, administration, contraindications and/orwarnings concerning the use of such therapeutic products. In oneembodiment, the label or package inserts indicates that the compositioncan be used for any of the purposes described herein.

With respect to the first embodiment (embodiment A), the dosagetypically required of the DPP-4 inhibitors mentioned herein inembodiment A when administered intravenously is 0.1 mg to 10 mg,preferably 0.25 mg to 5 mg, and when administered orally is 0.5 mg to100 mg, preferably 2.5 mg to 50 mg or 0.5 mg to 10 mg, more preferably2.5 mg to 10 mg or 1 mg to 5 mg, in each case 1 to 4 times a day. Thus,e.g. the dosage of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinewhen administered orally is 0.5 mg to 10 mg per patient per day,preferably 2.5 mg to 10 mg or 1 mg to 5 mg per patient per day.

A dosage form prepared with a pharmaceutical composition comprising aDPP-4 inhibitor mentioned herein in embodiment A contain the activeingredient in a dosage range of 0.1-100 mg. Thus, e.g. particular dosagestrengths of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineare 0.5 mg, 1 mg, 2.5 mg, 5 mg and 10 mg.

With respect to the second embodiment (embodiment B), the doses of DPP-4inhibitors mentioned herein in embodiment B to be administered tomammals, for example human beings, of, for example, approximately 70 kgbody weight, may be generally from about 0.5 mg to about 350 mg, forexample from about 10 mg to about 250 mg, preferably 20-200 mg, morepreferably 20-100 mg, of the active moiety per person per day, or fromabout 0.5 mg to about 20 mg, preferably 2.5-10 mg, per person per day,divided preferably into 1 to 4 single doses which may, for example, beof the same size. Single dosage strengths comprise, for example, 10, 25,40, 50, 75, 100, 150 and 200 mg of the DPP-4 inhibitor active moiety.

A dosage strength of the DPP-4 inhibitor sitagliptin is usually between25 and 200 mg of the active moiety. A recommended dose of sitagliptin is100 mg calculated for the active moiety (free base anhydrate) oncedaily. Unit dosage strengths of sitagliptin free base anhydrate (activemoiety) are 25, 50, 75, 100, 150 and 200 mg. Particular unit dosagestrengths of sitagliptin (e.g. per tablet) are 25, 50 and 100 mg. Anequivalent amount of sitagliptin phosphate monohydrate to thesitagliptin free base anhydrate is used in the pharmaceuticalcompositions, namely, 32.13, 64.25, 96.38, 128.5, 192.75, and 257 mg,respectively. Adjusted dosages of 25 and 50 mg sitagliptin are used forpatients with renal failure. Typical dosage strengths of the dualcombination of sitagliptin/metformin are 50/500 mg and 50/1000 mg.

A dosage range of the DPP-4 inhibitor vildagliptin is usually between 10and 150 mg daily, in particular between 25 and 150 mg, 25 and 100 mg or25 and 50 mg or 50 and 100 mg daily. Particular examples of daily oraldosage are 25, 30, 35, 45, 50, 55, 60, 80, 100 or 150 mg. In a moreparticular aspect, the daily administration of vildagliptin may bebetween 25 and 150 mg or between 50 and 100 mg. In another moreparticular aspect, the daily administration of vildagliptin may be 50 or100 mg. The application of the active ingredient may occur up to threetimes a day, preferably one or two times a day. Particular dosagestrengths are 50 mg or 100 mg vildagliptin. Typical dosage strengths ofthe dual combination of vildagliptin/metformin are 50/850 mg and 50/1000mg.

Alogliptin may be administered to a patient at a daily dose of between 5mg/day and 250 mg/day, optionally between 10 mg and 200 mg, optionallybetween 10 mg and 150 mg, and optionally between 10 mg and 100 mg ofalogliptin (in each instance based on the molecular weight of the freebase form of alogliptin). Thus, specific dosage amounts that may be usedinclude, but are not limited to 10 mg, 12.5 mg, 20 mg, 25 mg, 50 mg, 75mg and 100 mg of alogliptin per day. Alogliptin may be administered inits free base form or as a pharmaceutically acceptable salt form.

Saxagliptin may be administered to a patient at a daily dose of between2.5 mg/day and 100 mg/day, optionally between 2.5 mg and 50 mg. Specificdosage amounts that may be used include, but are not limited to 2.5 mg,5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg and 100 mg of saxagliptinper day. Typical dosage strengths of the dual combination ofsaxagliptin/metformin are 2.5/500 mg and 2.5/1000 mg.

A special embodiment of the DPP-4 inhibitors of this invention refers tothose orally administered DPP-4 inhibitors which are therapeuticallyefficacious at low dose levels, e.g. at oral dose levels <100 mg or <70mg per patient per day, preferably <50 mg, more preferably <30 mg or <20mg, even more preferably from 1 mg to 10 mg, particularly from 1 mg to 5mg (more particularly 5 mg), per patient per day (if required, dividedinto 1 to 4 single doses, particularly 1 or 2 single doses, which may beof the same size, preferentially, administered orally once- or twicedaily (more preferentially once-daily), advantageously, administered atany time of day, with or without food. Thus, for example, the daily oralamount 5 mg BI 1356 can be given in a once daily dosing regimen (i.e. 5mg BI 1356 once daily) or in a twice daily dosing regimen (i.e. 2.5 mgBI 1356 twice daily), at any time of day, with or without food.

A particularly preferred DPP-4 inhibitor to be emphasized within themeaning of this invention is1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine(also known as BI 1356). BI 1356 exhibits high potency, 24 h duration ofaction, and a wide therapeutic window. In patients with type 2 diabetesreceiving multiple oral doses of 1, 2.5, 5 or 10 mg of BI 1356 oncedaily for 12 days, BI 1356 shows favourable pharmacodynamic andpharmacokinetic profile (see e.g. Table 1 below) with rapid attainmentof steady state (e.g. reaching steady state plasma levels (>90% of thepre-dose plasma concentration on Day 13) between second and fifth day oftreatment in all dose groups), little accumulation (e.g. with a meanaccumulation ratio R_(A,AUC)≦1.4 with doses above 1 mg) and preserving along-lasting effect on DPP-4 inhibition (e.g. with almost complete(>90%) DPP-4 inhibition at the 5 mg and 10 mg dose levels, i.e. 92.3 and97.3% inhibition at steady state, respectively, and >80% inhibition overa 24 h interval after drug intake), as well as significant decrease in 2h postprandial blood glucose excursions by ≧80% (already on Day 1) indoses ≧2.5 mg, and with the cumulative amount of unchanged parentcompound excreted in urine on Day 1 being below 1% of the administereddose and increasing to not more than about 3-6% on Day 12 (renalclearance CL_(R,ss) is from about 14 to about 70 mL/min for theadministered oral doses, e.g. for the 5 mg dose renal clearance is about70 ml/min). In people with type 2 diabetes BI 1356 shows a placebo-likesafety and tolerability. With low doses of about ≧5 mg, BI 1356 acts asa true once-daily oral drug with a full 24 h duration of DPP-4inhibition. At therapeutic oral dose levels, BI 1356 is mainly excretedvia the liver and only to a minor extent (about <7% of the administeredoral dose) via the kidney. BI 1356 is primarily excreted unchanged viathe bile. The fraction of BI 1356 eliminated via the kidneys increasesonly very slightly over time and with increasing dose, so that therewill likely be no need to modify the dose of BI 1356 based on thepatients' renal function. The non-renal elimination of BI 1356 incombination with its low accumulation potential and broad safety marginmay be of significant benefit in a patient population that has a highprevalence of renal insufficiency and diabetic nephropathy.

TABLE 1 Geometric mean (gMean) and geometric coefficient of variation(gCV) of pharmacokinetic parameters of BI 1356 at steady state (Day 12)1 mg 2.5 mg 5 mg 10 mg Parameter gMean (gCV) gMean (gCV) gMean (gCV)gMean (gCV) AUC₀₋₂₄ 40.2 (39.7) 85.3 (22.7) 118 (16.0) 161 (15.7) [nmol· h/L] AUC_(T,ss) 81.7 (28.3) 117 (16.3) 158 (10.1) 190 (17.4) [nmol ·h/L] C_(max) [nmol/L] 3.13 (43.2) 5.25 (24.5) 8.32 (42.4) 9.69 (29.8)C_(max,ss) 4.53 (29.0) 6.58 (23.0) 11.1 (21.7) 13.6 (29.6) [nmol/L]t_(max)* [h] 1.50 [1.00-3.00] 2.00 [1.00-3.00] 1.75 [0.92-6.02] 2.00[1.50-6.00] t_(max,ss)* [h] 1.48 [1.00-3.00] 1.42 [1.00-3.00] 1.53[1.00-3.00] 1.34 [0.50-3.00] T_(1/2,ss) [h] 121 (21.3) 113 (10.2) 131(17.4) 130 (11.7) Accumulation 23.9 (44.0) 12.5 (18.2) 11.4 (37.4) 8.59(81.2) t_(1/2,) [h] R_(A,Cmax) 1.44 (25.6) 1.25 (10.6) 1.33 (30.0) 1.40(47.7) R_(A,AUC) 2.03 (30.7) 1.37 (8.2) 1.33 (15.0) 1.18 (23.4) fe₀₋₂₄[%] NC 0.139 (51.2) 0.453 (125) 0.919 (115) fe_(T,ss) [%] 3.34 (38.3)3.06 (45.1) 6.27 (42.2) 3.22 (34.2) CL_(R,ss) 14.0 (24.2) 23.1 (39.3) 70(35.0) 59.5 (22.5) [mL/min] *median and range [min-max] NC notcalculated as most values below lower limit of quantification

As different metabolic functional disorders often occur simultaneously,it is quite often indicated to combine a number of different activeprinciples with one another. Thus, depending on the functional disordersdiagnosed, improved treatment outcomes may be obtained if a DPP-4inhibitor is combined with active substances customary for therespective disorders, such as e.g. one or more active substancesselected from among the other antidiabetic substances, especially activesubstances that lower the blood sugar level or the lipid level in theblood, raise the HDL level in the blood, lower blood pressure or areindicated in the treatment of atherosclerosis or obesity.

The DPP-4 inhibitors mentioned above—besides their use inmono-therapy—may also be used in conjunction with other activesubstances, by means of which improved treatment results can beobtained. Such a combined treatment may be given as a free combinationof the substances or in the form of a fixed combination, for example ina tablet or capsule. Pharmaceutical formulations of the combinationpartner needed for this may either be obtained commercially aspharmaceutical compositions or may be formulated by the skilled manusing conventional methods. The active substances which may be obtainedcommercially as pharmaceutical compositions are described in numerousplaces in the prior art, for example in the list of drugs that appearsannually, the “Rote Liste®” of the federal association of thepharmaceutical industry, or in the annually updated compilation ofmanufacturers' information on prescription drugs known as the“Physicians' Desk Reference”.

Examples of antidiabetic combination partners are metformin;sulphonylureas such as glibenclamide, tolbutamide, glimepiride,glipizide, gliquidon, glibornuride and gliclazide; nateglinide;repaglinide; thiazolidinediones such as rosiglitazone and pioglitazone;PPAR gamma modulators such as metaglidases; PPAR-gamma agonists such asGI 262570; PPAR-gamma antagonists; PPAR-gamma/alpha modulators such astesaglitazar, muraglitazar, aleglitazar, indeglitazar and KRP297;PPAR-gamma/alpha/delta modulators; AMPK-activators such as AICAR;acetyl-CoA carboxylase (ACC1 and ACC2) inhibitors;diacylglycerol-acetyltransferase (DGAT) inhibitors; pancreatic beta cellGCRP agonists such as SMT3-receptor-agonists and GPR119;11β-HSD-inhibitors; FGF19 agonists or analogues; alpha-glucosidaseblockers such as acarbose, voglibose and miglitol; alpha2-antagonists;insulin and insulin analogues such as human insulin, insulin lispro,insulin glusilin, r-DNA-insulinaspart, NPH insulin, insulin detemir,insulin zinc suspension and insulin glargin; Gastric inhibitory Peptide(GIP); amylin and amylin analogues (e.g. pramlintide or davalintide); orGLP-1 and GLP-1 analogues such as Exendin-4, e.g. exenatide, exenatideLAR, liraglutide, taspoglutide, lixisenatide (AVE-0010), LY-2428757 (aPEGylated version of GLP-1), LY-2189265 (GLP-1 analogue linked toIgG4-Fc heavy chain), semaglutide or albiglutide; SGLT2-inhibitors suchas KGT-1251; inhibitors of protein tyrosine-phosphatase (e.g.trodusquemine); inhibitors of glucose-6-phosphatase;fructose-1,6-bisphosphatase modulators; glycogen phosphorylasemodulators; glucagon receptor antagonists;phosphoenolpyruvatecarboxykinase (PEPCK) inhibitors; pyruvatedehydrogenasekinase (PDK) inhibitors; inhibitors of tyrosine-kinases (50mg to 600 mg) such as PDGF-receptor-kinase (cf. EP-A-564409, WO98/35958, U.S. Pat. No. 5,093,330, WO 2004/005281, and WO 2006/041976);glucokinase/regulatory protein modulators incl. glucokinase activators;glycogen synthase kinase inhibitors; inhibitors of theSH2-domain-containing inositol 5-phosphatase type 2 (SHIP2); IKKinhibitors such as high-dose salicylate; JNK1 inhibitors; protein kinaseC-theta inhibitors; beta 3 agonists such as ritobegron, YM 178,solabegron, talibegron, N-5984, GRC-1087, rafabegron, FMP825;aldosereductase inhibitors such as AS 3201, zenarestat, fidarestat,epalrestat, ranirestat, NZ-314, CP-744809, and CT-112; SGLT-1 or SGLT-2inhibitors, such as e.g. dapagliflozin, sergliflozin, atigliflozin,canagliflozin or(1S)-1,5-anhydro-1-[3-(1-benzothiophen-2-ylmethyl)-4-fluorophenyl]-D-glucitol;KV 1.3 channel inhibitors; GPR40 modulators; SCD-1 inhibitors; CCR-2antagonists; dopamine receptor agonists (bromocriptine mesylate[Cycloset]); sirtuin stimulants; and other DPP IV inhibitors.

Metformin is usually given in doses varying from about 500 mg to 2000 mgup to 2500 mg per day using various dosing regimens from about 100 mg to500 mg or 200 mg to 850 mg (1-3 times a day), or about 300 mg to 1000 mgonce or twice a day, or delayed-release metformin in doses of about 100mg to 1000 mg or preferably 500 mg to 1000 mg once or twice a day orabout 500 mg to 2000 mg once a day. Particular dosage strengths may be250, 500, 625, 750, 850 and 1000 mg of metformin hydrochloride.

A maximal tolerated dose with regard to metformin is for example 2000 mgper day, 1500 mg per day (for example in asian countries) or 850 mgthree times a day or any equivalent thereof.

A dosage of pioglitazone is usually of about 1-10 mg, 15 mg, 30 mg, or45 mg once a day.

Rosiglitazone is usually given in doses from 4 to 8 mg once (or dividedtwice) a day (typical dosage strengths are 2, 4 and 8 mg).

Glibenclamide (glyburide) is usually given in doses from 2.5-5 to 20 mgonce (or divided twice) a day (typical dosage strengths are 1.25, 2.5and 5 mg), or micronized glibenclamide in doses from 0.75-3 to 12 mgonce (or divided twice) a day (typical dosage strengths are 1.5, 3, 4.5and 6 mg).

Glipizide is usually given in doses from 2.5 to 10-20 mg once (or up to40 mg divided twice) a day (typical dosage strengths are 5 and 10 mg),or extended-release glipizide in doses from 5 to 10 mg (up to 20 mg)once a day (typical dosage strengths are 2.5, 5 and 10 mg).

Glimepiride is usually given in doses from 1-2 to 4 mg (up to 8 mg) oncea day (typical dosage strengths are 1, 2 and 4 mg).

A dual combination of glibenclamide/metformin is usually given in dosesfrom 1.25/250 once daily to 10/1000 mg twice daily (typical dosagestrengths are 1.25/250, 2.5/500 and 5/500 mg).

A dual combination of glipizide/metformin is usually given in doses from2.5/250 to 10/1000 mg twice daily (typical dosage strengths are 2.5/250,2.5/500 and 5/500 mg).

A dual combination of glimepiride/metformin is usually given in dosesfrom 1/250 to 4/1000 mg twice daily.

A dual combination of rosiglitazone/glimepiride is usually given indoses from 4/1 once or twice daily to 4/2 mg twice daily (typical dosagestrengths are 4/1, 4/2, 4/4, 8/2 and 8/4 mg).

A dual combination of pioglitazone/glimepiride is usually given in dosesfrom 30/2 to 30/4 mg once daily (typical dosage strengths are 30/4 and45/4 mg).

A dual combination of rosiglitazone/metformin is usually given in dosesfrom 1/500 to 4/1000 mg twice daily (typical dosage strengths are 1/500,2/500, 4/500, 2/1000 and 4/1000 mg).

A dual combination of pioglitazone/metformin is usually given in dosesfrom 15/500 once or twice daily to 15/850 mg thrice daily (typicaldosage strengths are 15/500 and 15/850 mg).

The non-sulphonylurea insulin secretagogue nateglinide is usually givenin doses from 60 to 120 mg with meals (up to 360 mg/day, typical dosagestrengths are 60 and 120 mg); repaglinide is usually given in doses from0.5 to 4 mg with meals (up to 16 mg/day, typical dosage strengths are0.5, 1 and 2 mg). A dual combination of repaglinide/metformin isavailable in dosage strengths of 1/500 and 2/850 mg.

Acarbose is usually given in doses from 25 to 100 mg with meals.Miglitol is usually given in doses from 25 to 100 mg with meals.

Examples of combination partners that lower the lipid level in the bloodare HMG-CoA-reductase inhibitors such as simvastatin, atorvastatin,lovastatin, fluvastatin, pravastatin, pitavastatin and rosuvastatin;fibrates such as bezafibrate, fenofibrate, clofibrate, gemfibrozil,etofibrate and etofyllinclofibrate; nicotinic acid and the derivativesthereof such as acipimox; PPAR-alpha agonists; PPAR-delta agonists;inhibitors of acyl-coenzyme A:cholesterolacyltransferase (ACAT; EC2.3.1.26) such as avasimibe; cholesterol resorption inhibitors such asezetimib; substances that bind to bile acid, such as cholestyramine,colestipol and colesevelam; inhibitors of bile acid transport; HDLmodulating active substances such as D4F, reverse D4F, LXR modulatingactive substances and FXR modulating active substances; CETP inhibitorssuch as torcetrapib, JTT-705 (dalcetrapib) or compound 12 from WO2007/005572 (anacetrapib); LDL receptor modulators; MTP inhibitors (e.g.lomitapide); and ApoB100 antisense RNA.

A dosage of atorvastatin is usually from 1 mg to 40 mg or 10 mg to 80 mgonce a day

Examples of combination partners that lower blood pressure arebeta-blockers such as atenolol, bisoprolol, celiprolol, metoprolol andcarvedilol; diuretics such as hydrochlorothiazide, chlortalidon,xipamide, furosemide, piretanide, torasemide, spironolactone,eplerenone, amiloride and triamterene; calcium channel blockers such asamlodipine, nifedipine, nitrendipine, nisoldipine, nicardipine,felodipine, lacidipine, lercanipidine, manidipine, isradipine,nilvadipine, verapamil, gallopamil and diltiazem; ACE inhibitors such asramipril, lisinopril, cilazapril, quinapril, captopril, enalapril,benazepril, perindopril, fosinopril and trandolapril; as well asangiotensin II receptor blockers (ARBs) such as telmisartan,candesartan, valsartan, losartan, irbesartan, olmesartan and eprosartan.

A dosage of telmisartan is usually from 20 mg to 320 mg or 40 mg to 160mg per day.

Examples of combination partners which increase the HDL level in theblood are Cholesteryl Ester Transfer Protein (CETP) inhibitors;inhibitors of endothelial lipase; regulators of ABC1; LXRalphaantagonists; LXRbeta agonists; PPAR-delta agonists; LXRalpha/betaregulators, and substances that increase the expression and/or plasmaconcentration of apolipoprotein A-I.

Examples of combination partners for the treatment of obesity aresibutramine; tetrahydrolipstatin (orlistat); alizyme (cetilistat);dexfenfluramine; axokine; cannabinoid receptor 1 antagonists such as theCB1 antagonist rimonobant; MCH-1 receptor antagonists; MC4 receptoragonists; NPY5 as well as NPY2 antagonists (e.g. velneperit); beta3-ARagonists such as SB-418790 and AD-9677; 5HT2c receptor agonists such asAPD 356 (lorcaserin); myostatin inhibitors; Acrp30 and adiponectin;steroyl CoA desaturase (SCD1) inhibitors; fatty acid synthase (FAS)inhibitors; CCK receptor agonists; Ghrelin receptor modulators; Pyy3-36; orexin receptor antagonists; and tesofensine; as well as the dualcombinations bupropion/naltrexone, bupropion/zonisamide,topiramate/phentermine and pramlintide/metreleptin.

Examples of combination partners for the treatment of atherosclerosisare phospholipase A2 inhibitors; inhibitors of tyrosine-kinases (50 mgto 600 mg) such as PDGF-receptor-kinase (cf. EP-A-564409, WO 98/35958,U.S. Pat. No. 5,093,330, WO 2004/005281, and WO 2006/041976); oxLDLantibodies and oxLDL vaccines; apoA-1 Milano; ASA; and VCAM-1inhibitors.

The present invention is not to be limited in scope by the specificembodiments described herein. Various modifications of the invention inaddition to those described herein may become apparent to those skilledin the art from the present disclosure. Such modifications are intendedto fall within the scope of the appended claims.

All patent applications cited herein are hereby incorporated byreference in their entireties.

Further embodiments, features and advantages of the present inventionmay become apparent from the following examples. The following examplesserve to illustrate, by way of example, the principles of the inventionwithout restricting it.

EXAMPLES

BI 1356, a Potent and Selective DPP-4 Inhibitor, is Safe and Efficaciousin Patients with Inadequately Controlled Type 2 Diabetes DespiteMetformin Therapy

Efficacy and safety of BI 1356 (1, 5, or 10 mg qd), a potent andselective dipeptidyl peptidase-4 (DPP-4) inhibitor, was examined ininadequately controlled, metformin-treated (MET, ≧1 g daily) type 2diabetic patients (T2DM; HbA1c at baseline 7.5-10.0%). Effects werecompared to add-on of placebo (PBO) or of open label glimepiride (GLIM;1 to 3 mg qd) in a 12-week randomized, double-blind study. Antidiabeticmedication other than metformin was washed out for 6 weeks (34.7% of thepatients).

The primary endpoint was change from baseline in HbA1c, adjusted forprior antidiabetic medication. 333 patients (mean baseline HbA1c 8.3%;fasting plasma glucose [FPG] 185 mg/dL) were randomized to BI 1356, PBOor open-label GLIM. After 12 weeks, BI 1356 treatment resulted insignificant placebo corrected mean reductions in HbA1c (BI 1356 1 mg,n=65, −0.39%; 5 mg, n=66, −0.75%; 10 mg, n=66, −0.73%). Patientsreceiving GLIM demonstrated a slightly greater mean PBO correctedreduction in HbA1c at Week 12 (n=64, −0.90%). Reductions in FPG frombaseline to Week 12 with BI 1356 were statistically significant (1 mg,−19 mg/dL; 5 mg, −35 mg/dL; 10 mg, −30 mg/dL). Hence, a dose-responserelationship was demonstrated for HbA1c and FPG, reaching an effectplateau at 5 mg of BI 1356. For this dose, >80% DPP-4 inhibition attrough in >80% of the patients at week 12 was achieved.

In total, 106 patients (43.1%) experienced adverse events (AEs) withsimilar incidences across all treatments. Most frequently reportedepisodes were nasopharyngitis (7.5%), diarrhoea (3.3%), and nausea(3.0%). Drug-related hypoglycaemia did not occur with BI 1356 or PBO butin 3 patients receiving GLIM. Ten patients (3.7%) experienced seriousAEs but none of these events were considered drug-related.

The addition of BI 1356 to MET in patients with T2DM inadequatelycontrolled on MET alone achieved clinically relevant and statisticallysignificant reductions in HbA1c. Combination treatment with BI 1356 1,5, and 10 mg and MET was well tolerated and no case of hypoglycaemia wasreported. The incidence of AEs was comparable with BI 1356 and PBO.

BI 1356, a Potent and Selective DPP-4 Inhibitor, does not Prolong the QTinterval when Given in Therapeutic and 20-Fold Supratherapeutic Doses

A thorough QT study of BI 1356, a potent and selective dipeptidylpeptidase-4 inhibitor, was performed in healthy female and malesubjects, using 5 mg (therapeutic dose) and 100 mg. The study was arandomised, single-dose, placebo-controlled, double-blind, four-waycrossover study with open-label moxifloxacin (400 mg) as positivecontrol. Triplicate 12-lead electrocardiograms (ECGs) of 10 seconds'duration were recorded for all subjects pre-dose and at various timepoints over a 24-h period after each treatment. The primary parameterwas the subject-specific heart rate corrected QT interval (QTcI).

Forty-four subjects were enrolled, 26 (59.1%) of whom were male. Themean age was 36.4 years (range 22 to 48 years). The maximum gMeanconcentration after single oral administration was 7.05 nM (28.5% gCV)for 5 mg BI 1356, and 267 nM (66.6% gCV) for 100 mg BI 1356.

The upper limits of the one-sided 95% confidence intervals of theadjusted mean QTcI change from baseline (1-4 h) of BI 1356 compared withplacebo were 0.5 ms (5 mg) and −0.9 ms (100 mg) with mean estimates of−1.1 and −2.5 ms, respectively. Over the 24 h observation period, themaximum upper limits of the one-sided 95% confidence intervals for theadjusted QTcI changes from baseline compared with placebo were below 2.5ms for both doses and thus well below the non-inferiority margin of 10ms. Assay sensitivity of the trial was shown by the largest estimatedeffect size of the QTcI difference between moxifloxacin and placebobeing 10.5 ms with a lower limit of the two-sided 90% confidenceinterval of 8.1 ms.

There were no notable changes in heart rate or other ECG parameters, andoverall the safety assessment yielded similar results for alltreatments.

In summary, single dose administration of therapeutic (5 mg) andsupratherapeutic (100 mg) doses of BI 1356 did not prolong the QTinterval. The supratherapeutic dose resulted in maximum plasmaconcentrations that were about 38-fold higher than those obtained afterthe administration of the therapeutic dose of 5 mg, providing furthersupport for the unique safety profile of BI 1356 within the class ofDPP-4 inhibitors.

1. A method for improving glycemic control in type 2 diabetes patientswith inadequate glycemic control despite metformin therapy, said methodcomprising orally administering1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineto said patients in an amount of from 1 mg to 10 mg per day.
 2. Themethod according to claim 1, wherein said1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineis administered in an amount of 5 mg per patient per day.
 3. The methodaccording to claim 1 wherein the amount of metformin administered tosaid patient is in the amount of ≧1 g metformin per day, wherein said1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineis administered in an amount of 5 mg once daily.
 4. The method accordingto claim 1, wherein said1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineis administered in an amount of 5 mg per patient per day in combinationwith metformin.
 5. The method according to claim 1 wherein said patientshave HbA1c at baseline from 7.5 to 10% despite mono-medication with ≧1 gmetformin per day, and wherein said1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineis administered over 12 weeks in an amount of 5 mg once daily as add-onto metformin.
 6. The method according to claim 1, characterized in thatsaid1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineresults in >80% DPP-4 inhibition in >80% of said patients.
 7. (canceled)8. The method according to claim 4 wherein said patients have HbA1c atbaseline from 7.5 to 10% despite mono-medication with ≧1 g metformin perday, wherein said1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineis administered over 12 weeks in an amount of 5 mg once daily as add-onto metformin, characterized in that said administration results in−0.75% placebo corrected mean reduction in HbA1c from mean baselineHbA1c 8.3%, and/or said administration results in −35 mg/dL placebocorrected mean reduction in FPG from mean baseline FPG 185 mg/dL.
 9. Amethod for improving glycemic control in type 2 diabetes patients withinadequate glycemic control despite metformin therapy, said methodcomprising administering1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineorally in an amount of 5 mg per patient per day thereby resultingin >80% DPP-4 inhibition in >80% of said patients.
 10. A method fortreating patients having type 2 diabetes patients with inadequateglycemic control having HbA1c at baseline from 7.5 to 10% despitemono-medication with ≧1 g metformin per day, wherein1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineis administered over 12 weeks in an amount of 5 mg orally once daily asadd-on to metformin to said patients, and wherein >80% of said patientsexhibit >80% DPP-4 inhibition.
 11. A method for treating type 2 diabetespatients with inadequate glycemic control having HbA1c at baseline from7.5 to 10% despite mono-medication with ≧1 g metformin per day, themethod comprising administering1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineover 12 weeks in an amount of 5 mg orally once daily as add-on tometformin to said patients, wherein administration in said patientsresults in −0.75% placebo corrected mean reduction in HbA1c from meanbaseline HbA1c 8.3%, and/or administration in said patients results in−35 mg/dL placebo corrected mean reduction in FPG from mean baseline FPG185 mg/dL.
 12. The method according to claim 1, wherein said patientshave HbA1c at baseline ≧9%.
 13. The method according to claim 1, whereinthe method further improves insulin sensitivity and/or pancreatic betacell function in said patients. 14-18. (canceled)
 19. The methodaccording to claim 1, wherein said1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineis to be administered at any time of day.
 20. The method according toclaim 1, wherein said1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineis to be administered with or without food.
 21. The method according toclaim 1, wherein said1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineis administered in an amount of 5 mg once daily per patient.
 22. Themethod according to claim 1, wherein said1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineis administered in an amount of 2.5 mg twice daily per patient.